Researchers have discovered a new cause of a rare condition known as cblC, in which patients can’t process vitamin B12, leading to severe health problems. They report the condition, which they named “epi-cblC,” in patients from Europe and the United States.

Vitamin B12, or cobalamin (cbl), is essential for healthy functioning of the human nervous system and red blood cell synthesis. Unable to produce the vitamin itself, the human body has to obtain it from animal-based foods such as milk products, eggs, red meat, chicken, fish, and shellfish—or vitamin supplements. Vitamin B12 is not found in vegetables.

Rare hereditary recessive diseases were thought to appear in offspring only when both parents carry a mutation in the causal gene, but the findings challenge this paradigm.

cblC is usually the result of two mutations—one inherited from each parent—in a gene called MMACHC. In some patients, the scientists found this disease actually results from a mutation on a single copy of the gene and the silencing of the second copy by a gene modification referred to as epimutation. This epimutation is produced by a mutation in an adjacent gene.

The findings, which appear in Nature Communications, may have an impact on diagnosis, and genetic counseling in families with genetic diseases, as well as in the development of new therapeutic approaches.

Trouble in an adjacent gene

“We described a distinct and totally new mechanism referred as epi-cblC, whereby an epimutation causes abnormal regulation of the expression of an important vitamin B12 gene. This can result in a serious genetic disease that can cause anemia, neuro-cognitive impairment, and even early death,” says the study’s lead-author, Jean-Louis Guéant, director of the Inserm unit of Nutrition-Genetics-Environmental Risks at University of Lorraine in France and head of the department of molecular medicine and personalized therapeutics at the National Center of Inborn Errors of Metabolism at the University Regional Hospital of Nancy.

“…the study of patients with rare diseases is essential to the advancement of our knowledge of human biology.”

cblC is the most common of the inborn genetic errors of vitamin B12 metabolism. Based on one newborn patient, who died from clinical implications of this disease, the scientists from the University of Lorraine identified an epimutation affecting the MMACHC gene that was present in three generations and in the sperm of the fathers of two of the seven patients. Co-investigators subsequently found it in other cases from Europe and North America and discovered that it resulted from the altered reading of the adjacent gene.

“This epimutation observed in patients causes MMACHC to shut down and become inactive. This has the same effect as an actual mutation in the gene itself. This mechanism may be involved in many more diseases,” explains coauthor David Rosenblatt, a scientist in the Child Health and Human Development Program at the Research Institute of the McGill University Health Centre and chair in the department of human genetics at McGill University.

Hunting for epimutations

In previous work, the researchers at the RI-MUHC and McGill discovered that mutations in the MMACHC gene were responsible for the cblC inborn error of vitamin B12 metabolism. Following the study of several hundred patients, there remained a small number in whom only one mutation could be found in MMACHC.

Geneticists and molecular biologists will now need to look for epimutations in patients who have severe forms of rare diseases despite the lack of mutation in one of the two copies of the gene. The mechanism responsible for epimutation involves the two neighboring genes of MMACHC, the gene responsible for the disease.

Epigenetic mechanisms can also result from the environment (diet, stress, exposure to toxic products), and not by the chance of genetic mutations.

“We have identified some 40 rare diseases where this mechanism can be produced at the level of similar trios of genes,” says Gueant.

“It points out that the study of patients with rare diseases is essential to the advancement of our knowledge of human biology,” adds Rosenblatt, the director of one of the referral laboratories in the world for patients suspected of having this genetic inability to absorb vitamin B12.

The Region Lorraine, i-SITE Lorraine University of Excellence (LUE), the French National Institute of Health and Medical Research (Inserm), and the Canadian Institutes for Health Research (CIHR) supported the work.